Receptors for the Fc portion of IgG (FcgammaR) are expressed on most hematopoietic cell types. By binding antigen specific immunoglobulins, they provide an important link between the intra and extracellular compartments and are essential for the interactions between cells of the non adaptive (innate) and the adaptive systems of defense. They belong to an heterogeneous family of membrane receptors and mediate a wide array of cellular responses to antibody antigen complexes. The diversity of these responses is the result of the structural heterogeneity of the FcgammaR, related to differences in their intracytoplasmic domains, and to the presence, within the receptor complex, or receptor associated molecules that are important both for receptor expression and signal transduction. We have demonstrated that the low affinity receptor for IgG expressed on Natural Killer (NK) cells and macrophages (FcgammaRIIIA) transmembrane glycoprotein that, upon ligand binding, regulates functions of these cells by transducing signals that result in cell activation. Its counterpart on polymorphonuclear neutrophils (FcgammaRIIIB), a glycosilphosphatidylinositol linked molecule, is devoid of such functions. NK cell activation induced via FcgammaRIII primarily depends on induced activation of kinases. The working hypothesis of this proposal is that distinct specialized effector functions are mediated by different FcgammaR types, that depend on induction of distinct biochemical events in the same or different cell types, and that interactions of FcgammaR with other proteins cooperate in this function. In order to elucidate the role of the different types of FcgammaR on NK cells, myelomonocytic cells, and lymphocytes, we propose: 1) to identify those molecules that, activated upon interaction of FcgammaRIII on NK cells with its ligands, regulate signal transduction, and 2) to analyze functional role, an the mechanisms regulating them, of distinct FcgammaR types on B lymphocytes and myelomonocytic cells. Specifically, we propose to identify the kinases activated upon FcgammaRIII-ligand binding. The role of the substrates for these kinases, and of phosphatases, in controlling FcGgammaRIII-mediated signal transduction will also be analyzed. The molecular events occurring in myeloid/monocytic cells and B lymphocytes upon immune complexes binding will be studied and the interactions between different FcgammaR expressed on the same cell types will be dissected, to determine the relative role played by FcgammaRII on these cells. These studies are expected to result in the identification of common or distinctive features of behavior of FcgammaR, to provide information on FcgammaR-dependent functions on hematopoietic cells, and to pose the basis for understanding the mechanisms by which functions of cells of the innate system of defense are regulated.